Scleroderma (Systemic Sclerosis; SSc) is a relatively rare and often fatal disorder that affects mostly adult women. SSc is characterized by microvasculature damage, inflammation and autoimmunity, and fibroblasts activation leading to massive fibrosis in the connective tissue of skin, vessels, muscles and visceral organs. Organ involvement, disease progression and clinical severity vary greatly amongst affected individuals, with death occurring as the result of end-stage organ failure. In spite of significant effort, SSc pathogenesis remains ill-defined and consequently, disease outcome is often unpredictable and clinical treatment is very limited. Authors have discovered in the serum of patients affected by some autoimmune diseases, a new type of autoantibodies, targeting the human PDGF receptor (PDGFR) (WO2007/013124). Serum anti-PDGFR auto-antibodies may represent a main determinant of the pro-fibrotic phenotype of scleroderma fibroblasts, since they can convert healthy human fibroblasts into SSc-like cells characterized by excessive reactive oxygen species (ROS) production, stabilization of Ha-Ras, and amplified transcription of collagen genes (Baroni S S et al. N Engl J Med 2006; 354: 2667-2676).
PDGFR alpha and beta each contains five extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain. Ligand binding to the extracellular domains induces receptor dimerization and tyrosine phosphorylation, activating several downstream signaling pathways (Heldin C H, Biochimica et Biophysica Acta 1998), some of which are directly or indirectly linked to extracellular matrix regulation. Recently, a study by Olson and Soriano (Olson L E, Soriano P. Dev Cell 2009; 16: 303-313) has confirmed the central role of increased PDGFR activation and signaling in driving systemic fibrosis in vivo in transgenic mice.